Isoindolo(7,1,2-hij)quinolines

ABSTRACT

ISOINDOLO(7,1,2-HIJ)QUINOLINES ARE PROVIDED HAVING THE STRUCTURE   1-R5,1-R6,2-R1,2-R2,3-R3,3-R4,X,Y-1,2,3,5-TETRAHYDRO-   ISOINDOLO(7,1,2-HIJ)QUINOLIN-5-ONE   WHEREIN R5 CAN BE HYDROXYL, HALOGEN, SUBSTITUTED AMINO, ALKOXY, ACYLOXY, AROYLOXY, SUBSTITUTED AMIDO, AND AMINOSUBSTITUTED AMIDO; AND R6 IS HYDROGEN; AND R5 AND R6 CAN BE TAKEN TOGETHER TO FORM =O; X, Y, R1, R2, R3 AND R4 ARE AS DEFINED BELOW; AND WHICH ARE ANTI-INFLAMMATORY AGENTS, CENTRAL NERVOUS SYSTEM DEPRESSANTS, INHIBITORS OF CYCLIC AMP PHOSPHODIESTERASE AND SUN-SCREENING AGENTS.

United States Patent 3,819,624 ISOINDOL0[7,1,2-hij1QUINOLlNES Seymour D. Levine, North Brunswick, N.J., assiguor to E. R. Squibb & Sons, Inc., Princeton, NJ. N0 Drawing. Filed Jan. 3, 1972, Ser. No. 215,189 Int. Cl. C07d 27/30 US. Cl. 260-2472 A 4 Claims ABSTRACT OF THE DISCLOSURE Isoindolo[7,1,2-hij]quinolines are provided having the structure wherein R can be hydroxyl, halogen, substituted amino, alkoxy, acyloxy, aroyloxy, substituted amido, and aminosubstituted amido; and R is hydrogen; and R and R can be taken together to form =0; X, Y, R R R and R are as defined below; and which are anti-inflammatory agents, central nervous system depressants, inhibitors of cyclic AMP phosphodiesterase and sun-screening agents.

This invention relates to isoindolo[7,1,2-hij]quinolines having the structure I Rs 34 R2 12 NTO RJ wherein X or Y can be hydrogen, halogen, nitro, lower alkyl, lower alkoxy, aryl or substituted amino and at least one of X and Y is hydrogen; R R R -and R are the same or dilferent and can be hydrogen or lower alkyl; R is hydroxyl, halogen, lower alkoxy, acyloxy, aroyloxy,

substituted amino substituted amido and amino-substituted amido; R is hydrogen and R and R can be taken together to form =0; and acid-addition salts thereof where applicable.

R' and R may be the same or different and represent hydrogen, lower alkyl, aryl and alkenyl. Furthermore, R and R can be taken together with N to form a heterocyclic ring.

The term lower alkyl as employed herein includes both straight and branched chain radicals of up to and including eight carbon atoms, for instance, methyl, ethyl, propyl, isopropyl, butyl, s-butyl, tbutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl,2,2,4-trimethylpentyl and the like. The lower alkyl group can include substituents such as aryl, halo, hydroxyl, alkoxy, amino or substituted amino.

The term halogen includes F, Cl, Br or I.

The term aryl as employed herein includes monocyclic carbocyclic aryl radicals, for instance, phenyl and substituted phenyl radicals, such as lower alkylor alkoxyphenyl (e.g., 0-, m-, or p-tolyl, ethylphenyl, butylphenyl and the like), di(lower alkyl)phenyl (e.g., 2,4-dimethylphenyl, 3,5-diethylphenyl, and the like, and corresponding alkoxy compounds), halophenyl (e.g., chlorophenyl, bromophenyl, iodophenyl and fluorophenyl), 0-, mor p-nitrophenyl, dinitrophenyl (e.g., 3,5-dinitrophenyl, 2,6- dinitrophenyl, and the like), and trinitrophenyl (e.g., picryl), and aminophenyl, such as p-dimethylaminophenyl.

The acy or aryl portion of the acyloxy or aroyloxy group, respectively, is derived from a hydrocarbon carboxylic acid of less than twelve carbon atoms, which may be exemplified by the lower alkanoic acids (e.g., formic, acetic, propionic, butyric, valeric, trimethyl acetic and caproic acids), the lower alkenoic acids (e.g., acrylic, methacrylic, crotonic, 3-butenoic and senecioic acids), the monocyclic aryl-carboxylic acids (e.g., benzoic and toluic acids), the monocyclic aryl-lower alkanoic acids [e.g., phenacetic, ,B-phenylpropionic, a-phenylbutyric, and 5-(p-methylphenyl)pentanoic acids], the cycloalkyl carboxylic acids (e.g., cyclobutane carboxylic acid, cyclopentane carboxylic acid and cyclohexane carboxylic acid), the cycloalkenyl carboxylic acids (e.g., 2-cyclobutene carboxylic acid and 3-cyclopentene carboxylic acid). the cyclopentene carboxylic acid), the cycloalkyl and cycloalkenyl-lower alkanoic acids [e.g., cyclohexaneacetic, a-cyclopentanebutyric, 2 cyclopenteneacetic and 3-(3-cyclohexene) pentenoic acids], and the like.

The term alkenyl includes mono-unsaturated straight chain or branched chain radicals of less than eight carbons corresponding to lower alkyl as defined above.

Examples of NR' R amino groups include monoor dilower alkyl-, arylalkyl-, lower alkylaryl-, alkenylor arylamino wherein lower alkyl and aryl are as defined herein, such as methylamino, ethylamino, isopropylamino, heptylamino, dimethylamino, diethylamino, ethylmethylamino, butylmethylamino, ethyl i-propylamino, allylamino, anilino, benzylamino, diphenylamino, naphthylamino, or N-methyl-N-phenylamino and the like.

NR' R can be taken together to form a heterocyclic radical having the formula in which X represents NR O, S or CH r represents 1, 2 or 3; R represents hydrogen, lower alkyl, hydroxylower alkyl, lower alkanoyloxy-lower alkyl, hydroxy-lower alkoxy-lower alkyl, di(lower alkyl)amino-lower alkoxylower alkyl, lower alkylamino-lower alkyl, di-lower alkyl amino-lower alkyl, amino-lower alkyl; and R represents any of the R groups. These may be exemplified by piperidinyl; (lower alkyl)piperidinyl [e.g., 2-, 3- or 4- (lower alkyl)piperidinyl]; (lower alkoxy)piperidinyl; pyrrolidinyl; (lower alkyl)-pyrrolidinyl; (lower alkoxy)pyrrolidinyl; piperazinyl; (lower alkyl) piperazinyl (e.g., N methylpiperazinyl); di(lower alkyl)piperazinyl; (lower alkoxy)piperazinyl; (hydroxy-lower alkyl)piperazinyl [e.g., N -(Z-hydroxyethyl)piperazinyl]; (lower alkanoyloxyalkyl) piperazinyl [e.g., N -(Z-acetoxyethyl)-piperazinyl]; (hydroxyJower alkoxy-lower alkyl)piperazinyl [e.g., N -[2-(2 hydroxyethoxy)ethyl]piperaziny1]; di-(lower alkyl)amino-(lower alkoxy-lower alkyl)piperazinyl [e.g., N [2- (Z-dimethylaminoethoxy) ethyl] piperazinyl] homopiperazinyl; amino(l0wer alkyl)piperidinyl [e.g., 3-(aminomethyl)piperidinyl], lower alkylamino (lower alkyl) piperidinyl [e.g., 2-[(methylamino)ethyl]piperidinyl], dilower alkylaminoflower alkyl) piperidinyl [e.g., 4-[(dimethylamino) methyl) Jpiperidinyl] The term amido as employed herein includes radicals of the structure wherein R can be lower alkyl, alkenyl, or aryl, substituted alkyl or substituted aryl, substituted with halogen, hydroxyl, alkoxy, amino or monoor disubstituted amino or a monocyclic heterocycle such as pyridyl, furyl, thiazolyl, thienyl or pyrryl. The disubstituted amino substituent of the alkyl may also form a 5 to 7 membered heterocycle which may have up to two hetero atoms, such as morpholino, pyrrolidino or piperidino.

The term amino-substituted amido includes radicals of the structure wherein n is 1 to 12 and (CH represent alkylene chains, that is, bivalent saturated straight or branched aliphatic groups, containing 1 to 12 carbons, corresponding to the above-mentioned lower alkyl groups and which may include lower alkyl and/or aryl side chains. Examples of such alkylene groups include methylene, ethylene, l-methylethylene, Z-methylethylene, tetramethylene, propylene, trimethylene, hexa-methylene, octamethylene, decamethylene, dodecamethylene, 3-methyldodecamethylene, dimethylethylene, l-phenylethylene and the like.

The salts of the compounds of this invention include the acid-addition salts, particularly the non-toxic acid-addition salts. Acids useful for preparing the acid-addition sa'lts, include inter alia, inorganic acids, such as the hydrohalic acids (e.g., hydrochloric and hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid, and organic acids, such as oxalic, maleic, fumaric, tartaric, citric, pamoic, acetic, and succinic acid.

Compounds of formula I wherein R and R are taken together to form =0 that is XOOY can be prepared by reacting a naphthostyril derivative of the structure VI R1 R8 can be prepared by reducing compound V above by reacting it with an alkali metal borohydride, such as NaBH KBH, or LiBI-I Compounds of formula I wherein R is halogen and R is hydrogen, that is VIII can be prepared by reacting compound VII above with a halogenating agent such as thionyl chloride, thionyl bromide, phosphorus trichloride or phosphorus tribromide.

Compounds of formula I wherein R is substituted amino (R R N) and R is hydrogen, that is can be prepared by reacting compound VIII above with an amine of the structure can be prepared by refluxing compound VIII above with a lower alkanol.

Compounds of formula I wherein R is substituted, amido, that is X KQ/IVY can be prepared by reacting compound VII above with a nitrile of the structure XIII R CN a in the presence of an acid, in a Ritter reaction wherein R is as defined hereinbefore.

Some specific examples of nitriles which are useful in the present invention are the following:

chloroform, carbon tetrachloride, hexane and nitrobenzene.

A variety of acids may be used to carry out the reac- HCN tion between compound VII and the nitrile. Examples CHSCN CHOCHzCHrCN 5 of suitable acids are sulfuric, perchloric, phosphoric, p0ly phosphoric, formic, substituted sulfonic acids and boron CHFCHCN CH3 trifiuonde. In general, concentrated sulfuric acid is preferred. HOCECHZCN NCHQCECN Compounds of formula I wherein ClCHzCHzCN C a ll CH CH 1 a a \NAJHQCEEON Rhs R MN (0111).. 0 NH /NCH2CH2CN that is 0113011, XIV

CHiO@ON on=onom N H R RN(CHa) -y}N CHs-@CN c1181 CN CH: X Y @CH:CN oar-@ornon wherein n is 1 to 4, can be prepared by reacting compound XII wherein R is (CH =Hal that is N-CHiCN R3 R4 NCHiCN V CH: RL- \N :0

N-CHaCN NCHzCN H Hal (C 2) m: N

N-CHnOHzCN o1--cn X 0 O Y an of v m y a e e a a e P Compounds of formula I wherein R is acyloxy or at about atmospheric pressure. Operable temperatures, aroyloxy and R6 is H that is however, may vary from about -20 C. to about 80 C., preferably from about 0 C. to about 60 C. and most preferably from about 25 C. to about 50 C. Operable R2 pressures may vary from about 0.2 atmosphere to about 5 atmospheres, preferably from about 0.5 atmosphere to about 2 atmospheres, and most preferably at about atmospheric pressure. The reaction time may vary from a few minutes to several days. Generally, reaction times will be from about 10 minutes to about 100 hours. Lower temperatures usually require longer reaction time.

While an excess of the nitrile is permissible, the nitrile and compound VII may also be employed in stoichiometric quantities, or with a slight excess of nitrile.

In the case of nitriles which are solid at room temperature, the reaction is preferably carried out in the pres ence of polar and non-polar solvents such as, for example, glacial acetic acid, acetic anhydride, di-n-butyl ether,

can be prepared by reacting compound VII with a carboxylic acid containing up to twelve carbons or an acid anhydride thereof or acyl or aroyl halide. Examples of such acids are set out hereinbefore.

Examples of starting naphthostyril derivatives which can be employed herein include, but are not limited to, the following set out in Table A below:

TABLE A QOOC--C- N I Q v. Y

R R R R X (position) Y (position) Q H H H H H B! (4) CzH H OH: H H H F (4) CH3 CH3 02115 H H H (4) CH3 H: CH3 CH3 H OCH: (4 CzH1 C2115 H H H N(CH3)2 (4) H CaH1 CaH1 H H Br (5) 04H: H C4Hn H C4Hn H F (5) H H H CH3 CH3 H I (5) H 05 05H H H H OCHa (5) CH3 CaHra H H H B1 (6) H 05H H H H F (6) H CaH CzHs H C2Hs H I (6) H H CH3 H H CHa C1 (6) H H C3H7 CH3 CH3 CaH- OCH: (6) H H 6H)! CH3 H CsHs (6) H C H; H CH: ClHa H (8) H H H CH3 H H 0511:. (8) H CH3 C2H5 CzHg H CH3 CH3 (8) H H H H 02H: (8) H CsH1 Other examples of naphthostyril derivative starting materials are set out in copending US. application Ser. No. 185,820, filed Oct. 1, 1971, entitled Naphthostyril Derivatives.

Examples of other starting reactants such as R' R NH, are set out in the working Examples.

The compounds of this invention possess central nervous system modifying activity, particularly as depressants and are therefore useful as tranquilizers. They may be administered orally or parenterally in the form of tablets, capsules, elixirs, injectables or the like by incorporating the appropriate dosage of the compound with carriers according to accepted pharmaceutical practice.

The dosage for various mammalian species would be from 25 to 250 mg. administered orally or parenterally once to several times daily, dependent upon the individual requirements of the recipient.

In addition, the compounds of the invention have been found to inhibit cyclic AMP phosphodiesterase, thereby providing an increase in the intracellular concentration of adenosine-3,5'-cyclic monophosphate. The administration of about to 900 mg./kg./day, preferably about 20 to 250 mg./kg., of the compounds of the invention in single or two to four divided doses in conventional oral or parenteral dosage forms such as those described above may be used to alleviate the symptoms of asthma.

Further, the compounds of the invention are useful as sunscreening agents.

The compounds of this invention are also useful as anti-inflammatory agents in warm blooded animals in a manner similar to indomethacin. They may be used to decrease joint swelling tenderness, pain and stiffness, in mammalion species, e.g., in conditions such as rheumatoid arthritis. A compound of formula I or a physiologically acceptable salt (when applicable) of the character described above may be compounded according to accepted pharmaceutical practice in oral dosage forms such as tablets, capsules, elixirs or powders for administration of about 100 mg. to 2 gm. per day, preferably 100 mg. to 1 gm. per day in two to four divided doses.

The following examples illustrate the present invention without, however, limiting the same thereto. All temperatures are expressed in C.

EXAMPLE 1 2,3-Dihydroisoindolo [7,1,2-hij] quinoline-1,5-dione A mixture of 260 mg. of 1,2-dihydro-2-oxobenz[ed]- indole-l-propionic acid in 12.5 ml. of polyphosphoric acid is stirred and heated at 100 for 1 hour. The mixture is poured into water, stirred and extracted with chloroform. The chloroform extracts are Washed with saturated sodium bicarbonate solution, 8% salt solution, dried and evaporated. Plate chromatography of the residue on neutral alumina using chloroform as the developing solvent gives a major yellow band which is eluted with ethyl acetate. Evaporation gives a residue which is crystallized from chloroform-isopropyl ether to give 117 mg. of the titled compound, m.p. 187l88. Recrystallization from the same solvents gives the analytical sample, m.p. 187.5- 188.5.

Anal.Calcd. for C H NO C, 75.32; H, 4.06; N, 6.28. Found: C, 75.21; H, 4.32; N, 6.14.

EXAMPLE 2 9-Chloro-2,S-dihydroisoindolo[7,1,2-hij]quinoline- 1,5-dione Following the procedure of Example 1, but employing V Anal.--Calcd. for C H ClNO C, 65.25; H, 3.13; N, 5.44; CI, 13.75. Found: C, 65.27; H, 3.40; N, 5.17; Cl, 14.00.

EXAMPLE 3 2,3-Dihydro-l-hydroxyisoindolo[7,1,2-hij] quinolin- 5 lip-one A solution of 117 mg. of 2,3-dihydroisoindolo[7,1,2- hij]quinoline-1,5-dione in 5 ml. of dioxane and 5 ml. of methanol is treated with 30 mg. of sodium borohydride and stirred at room temperature for 1 hour. The mixture is concentrated, diluted with water and extracted with chloroform. The extracts are washed with 8% salt solution, dried and evaporated. Plate chromatography of the residue on silica gel using chloroform-ethyl acetate as the developing solvent gives a major yellow band which is eluted with ethyl acetate. Evaporation gives a residue which is crystallized from chloroform-isopropyl ether to give mg. of the title compound, m.p. 162l63.5. Recrystallization from the same solvents gives the analytical sample, m.p. 163164.

Anal.-Calcd. for C H NO C, 74.65; H, 4.92; N, 6.22. Found: C, 74.55; H, 5.18; N, 6.21.

EXAMPLE 4 9-Chloro-2,3-dihydro-l-hydroxyisoindolo[7,1,2-hij] quinolin-S 1I I -one Following the procedure of Example 3, but employing 9 chloro-2,3-dihydroisoindolo[7,1,2-hij]quinoline-1,5-dione as the starting material, there is obtained the title compound, m.p. 240.5241.5.

AnaI.-Calcd. for C H ClNO C, 64.75; H, 3.88; N, 5.40; Cl, 13.65. Found: C, 64.54; H, 4.07; N, 5.19; Cl, 13.88.

EXAMPLE 5 1-Acetoxy-2,3-dihydroisoindolo [7,1,2-hij]quinolin- 5 1 f I -one A mixture of 200 mg. of 2,3-dihydro-l-hydroxyisoindolo[7,1,2-hij]quinolin-5(1 )-one in 1.5 ml. of pyridine and 1.5 ml. of acetic anhydride is allowed to react overnight. The mixture is poured into ice-Water and extracted with chloroform. The extracts are washed with 2N HC], and 8% salt solution, dried and evaporated. The residue is crystallized from ether-hexane to give 200 mg. of the title compound, m.p. IDS-106. Recrystallization from the same solvents gives the analytical sample, -106.

Anal.Calcd. for C H NO C, 71.90; H, 4.90; N, 5.13. Found: C, 71.61; H, 5.08; N, 5.24.

EXAMPLE 6 1-Chloro-2,3-dihydroisoindole[7,1,2-hij]quinolin- 5 1g) -one A mixture of 1.0 g. of 2,3-dihydro-l-hydroxyisoindolo- [7,1,2-hij]quinolin-5(1g)-one in 20 ml. of benzene is treated with 1.4 ml. of thionyl chloride and stirred overnight. The mixture is diluted with water and the benzene layer separated. The benzene fraction is washed with water, 8% salt solution, dried and evaporated to give the title compound.

EXAMPLE 7 1-Ethoxy-2,3-dihydroisoindolo[7,1,2-hij1quinolin- 5 1 I- I -one A mixture of 1.66 g. of 1-chloro-2,3-dihydroisoindolo- [7,1,2-hij]quinolin-5(1E)-one in 50 ml. of ethanol containing 1 ml. of triethylamine is refluxed for 2.5 hours. The solvents are evaporated, and the residue treated with water and extracted with chloroform. The chloroform extracts are washed with 8% salt solution, dried and evaporated. The residue is crystallized from isopropyl ether to provide 1.38 g. of the title compound, m.p. 95.5- 96.5". Recrystallization from isopropyl ether gives the analytical sample, 97-98.

Anal.-Calcd. for C H NO C, 75.87; H, 5.97; N, 5.53. Found: C, 75.95; H, 5.53; N, 5.31.

EXAMPLE 8 2,3-Dihydro-l-morpholinoisoindolo [7, 1,2-hij] quinolin-5(1 I1)-one A mixture of 1.66 g. of 1-chloro-2,3-dihydroisoindolo- [7,1,2-hij]quinolin5(1 I1)-one in 5 ml. of morpholine and 25 ml. of dioxane is refluxed overnight. The mixture is evaporated, treated with 2N HCl and extracted with chloroform. The acid solution is made alkaline with sodium hydroxide and extracted with chloroform. The chloroform extracts are washed with 8% salt solution, dried and evaporated. The residue is crystallized from chloroform-isopropyl ether to give 1.34 g. of the title compound, m.p. 172-173.

Anal.Calcd. for C H N O C, 73.45; H, 6.16; N, 9.52. Found: C, 73.21; H, 6.07; N, 9,49.

EXAMPLE 9 2,3-Dihydrl-pyrrolidinoisoindolo [7 1 ,2-hij quinolin 1g) -one, hydrochloride Following the procedure of Example 8, but employing pyrrolidine as the amine, and converting the product to the hydrochloride salt, there is obtained the title compound, m.p. 292-293 d.

Anal.Calcd. for C H ClN O: C, 68.68; H, 6.08; N, 8.90; CI, 11.26. Found: C, 68.52; H, 6.31; N, 8.65; CI, 11.52.

EXAMPLE 1-(Dimethylamino)-2,3-dihydroisoindolo[7,1,2-hij] quinolin-S 1 I -one, hydrochloride Following the procedure of Example 9, but employing diethylamine as the amine, there is obtained the title compound, m.p. 231.5232.5.

Anal.Calcd. for C H ClN O: C, 68.24; H, 6.68; N, 8.85; Cl, 11.19. Found: C, 67.90; H, 6.74; N, 9.15; CI, 11.23.

EXAMPLE l1 1,9-Dichloro-2,3 -dihydroisoindolo-[7,1,2-hij] quinolin- 5 1 I) -one A solution of 500 mg. of 2,3-dihydro-l-hydroxyisoindolo[7,1,2-hij]quinolin-5(1 1;)-one in 5 ml. of acetic acid is cooled in an ice-bath and treated with 0.25 ml. of sulfuryl chloride. After 30 minutes at room temperature, an additional 0.25 ml. of sulfuryl chloride is added and the mixture is stirred for 1.5 hour. The mixture is diluted with water and extracted with chloroform. The chloroform extracts are washed with 8% salt solution, dried and evaporated. Plate chromatography of the residue on silica gel using chloroform as the developing solvent gives a major yellow band which is eluted with ethyle acetate. Evaporation gives a residue which is crystallized from acetone-petroleum ether to afford 90 mg. of the title compound, m.p. 127-129. Recrystallization from the same solvents provides the analytical sample, m.p. 128- 129.

AnaL-Calcd. for C H Cl NO: C, 60.47; H, 3.23; N, 5.04; Cl, 25.50. Found: C, 60.77; H, 3.51; N, 4.98; Cl, 25.62.

10 EXAMPLE 12 9-Chloro-2,3-dihydro-l-pyrrolidinoisoindolo [7,1,2-hij] quinolin-S 15;) -one, hydrochloride A mixture of 3.1 g. of 1,9-dichloro-2,3-dihydroisoindolo[7,1,2-hij]quinolin-5(1g)-one in 50 ml. of dioxane and 10 ml. of pyrrolidine is refluxed overnight and evaporated. The residue is treated with 2N sodium hydroxide solution and extracted with chloroform. The chloroform extracts are washed with 8% salt solution, treated with charcoal, filtered and dried. The free base is dissolved in dimethoxyethane treated with methanolic HCl and the solid collected by filtration to aiford 1.53 g. of the title compound, m.p. 308-309" (1. Recrystallization from ethanol provides the analytical sample, m.p. 312-314 d.

Anal.--Calcd. for C H Cl N O z C, 61.90; H, 5.19; N, 8.02; Cl, 20.34. Found: C, 62.18; H, 5.36; N, 7.87; Cl, 20.54.

EXAMPLE 13 9Chloro-2,3-dihydro-l-mo-rpholinoisoindolo[7,1,2-hij] quinolin-S 1g -one, hydrochloride Following the procedure of Example 12, but employing morpholine as the base, there is obtained the title compound, m.p. 207-209 d.

Anal.-Calcd. for C H Cl N O C, 59.18; H, N, 7.66; Cl, 19.14. Found: C, 59.01; H, 5.21; N, 7.37; Cl, 19.25.

EXAMPLE 14 1-Acrylamido-2,3-dihydroisoindolo- [7,1,2-hij]quinolin-5 111) -one An ice-bath cooled suspension of 500 mg. of 2,3-dihydro-l-hydroxyisoindolo [7 1,2-hij1quinolin 5( l P I )-one in 5 ml. of acrylonitrile is treated dropwise with 1.5 ml. of concentrated sulfuric acid. The reaction mixture is stirred at room temperature for 2.5 hours, diluted with water and extracted with chloroform The chloroform extracts are washed with 8% salt solution, dried and evaporated. Crystallization from chloroform gives 442 mg. of the title compound, m.p. 234-235. Plate chromatography of this material on silica gel using chloroformethyl acetate (1:1) as the developing solvent gives a major yellow band, which is eluted with ethyl acetate. Evaporation and crystallization of the residue from chloroform gives the analytical sample, m.p. 237238.

Anal.Calcd. for C H N 'O C, 73.36; H, 5.07; N, 10.07. Found: C, 73.31; H, 4.98; N, 10.03.

EXAMPLE 15 1-Acetamido-2,3-dihydroisoindolo- [7,1,2-hij]quinolin-5(1I )-one Following the procedure of Example 14, but employing acetonitrile, there is obtained the title compound, m.p. 253-254".

Anal.-Calcd. for C H N O C, 72.16; H, 5.30; N, 10.52. Found: C, 71.89; H, 5.58; N, 10.43.

EXAMPLE 16 l-Benzamido-Z,3-dihydroisoincolo [7,1,2-hij1quinolin-5 1g) -one Following the procedure of Example 14, but employing benzonitrile, there is obtained the title compound, m.p. 261.5-2625".

Anal.Calcd. for C H N O C, 76.81; H, 4.91; N, 8.53. Found: C, 76.76; H, 4.95; N, 8.46.

EXAMPLE 17 EXAMPLES 31 TO 4 1-(3-Bromopropionamido)-2,3-dihydroisoindolo- Following the pfoclfvdufe of Example 3, but Substituting [7,1,2 hij]quino1in 5(lgyone the ketones prepared in Examples 21 to 30 for the ketone used in Example 3, the hydroxy compound in Table H Following the procedure of Example 14, but employing 5 b l i bt i d,

3-bromopropionitrile, there is obtained the titled com- TABLE H pound, m.p. 219-2195.

Anal.-Calcd. for C H BrN O c, 56.85; H, 4.21; Pmdm N, 7.80; Br, 22.25. Found: C, 57.10; H, 4.34; N, 7.73; Br, 22.45. R2

EXAMPLE 1-8 I= R1 2,3-Dihydro-1-(3-morpholinopropionamido)- isoindolo[7,1,2-hij]quinoline-5(1g)-one H0 X Y A solution of 650 mg. of 1-(3-bromopropionamido)-2,3-

dihydroisoindolo[7,1,2-hij]quinolin-5(lgyone in 15 ml. of ethanol and 1.3 ml. of morpholine is refluxed for 2 i g p hours. The mixture is concentrated and the solid collected X Y by filtration to give 458 mg. of the title compound, m.p. 1% g H H H ZOO-204. Recrystallization from chloroform-isopropyl 8%? 2? ether gives the analytical sample, m.p. 201-202. a 1 gH: gi GHE H Anal.-Calcd. for C H N O c, 69.02; H, 6.34; N, H H H Zfiifi" 11.50. Found: C, 69.22; H, 6.48; N, 11.66. E 8%! gm g gi -gr EXAMPLE 19 1 11, a g g-gorr, 2,3-Dihydrol- 3-( l-pyrrolidinyl propionamido] isoindolo[7,1,2-hij]quinolin-5(LED- EXAMPLES 41 TO 50 Following the procedure of Example 18, but employing Procedure f but i i l pyrrolidine as the amine, there is obtained the title comfor the 23'd1hydw'l'hydroxylsomdoloulz'hlflqumolm' Pound, 214415... 5(1I )-one, the compounds prepared in Examples 31 to Anal' calcd. for C21H23N3O2: C 72 18; H, 3; N, 40, the PI'OdllCt Shown below Table III iS obtained. 12.03. Found: C, 72.34; H, 6.88; N, 12.07. TABLE 11 EXAMPLE 20 R 1-[ 3- (Diethylamino propionamido] -2,3-dihydroisoin- N 0 dolo[7,1,2-hij]quinolin-5(1g)-one, hydrochloride l Hal Following the procedure of Example 18, but employing diethylamine as the amine and converting the prod- X Y uct to its hydrochloride salt, there is obtained the title compound, m.p. 238-239.

Anal. Calcd. for C H ClN O 2 C, 65.08; H, 6.75; N, R1 Ra a R4 X Y 51323; Cl, 9.14. Found: C, 64.86; H, 7.02; N, 11.08; Cl, 8% g EH 5 B EXAMPLES 21 o 30 0 H; CH; CH; 0 H: r 7-0CH:

a 2 2% 2 a a... Following the procedure of Example 1, but employing H H H B H H 8-0011: 1 the naphthostyril derivative shown in column 1 of Table I 2 E 3 E Z3? in place of 1,2-dihydro-2-oxobenz-[cd]-indole-l-propionic CH: OH: H Q-OCH: H acid, the product shown in column 2 is obtained. H H H H H TABLE I Column 1 Column 2 R Ra a 4 0 R1 O ooo d-o-N N l XWOI Q; X Y

Example No. Q R1 R2 R R X Y R R2 R R4 X Y OH H H H H H 0.11, H H 0.11, on: H A: B2; 881%.; i 81152; 8%; CH; CH; H 4-0CH As per Column 1 a 1 3 03111 CH; 6-CoH5- H As per Column 1 H H 04H, H H 4-N(CH:): As per Column 1 13 H H H H S-OCH; As per Column 1 2H, CH; 02H; CH; H 4-Br As per Column 1 a... a... 2. a 2...... if 1: 2; 821m B H H H 6-F H As Ber Column 1 13 14 EXAMPLES 51 TO 60 EXAMPLES 71 TO 80 Following the procedure of Example 5, but substituting Following the procedure of Example 8, but substituting the'l-hydroxy compound prepared in Example 31 to 40 the halonaphthostyril starting material prepared in Exand the acid, anhydride, or acyl or aroyl halide shown in column 1 of Table IV below, the product shown in column 5 2 is obtained.

TABLE IV Acid anhydride or acld or aroyl or aeyl halide 0 ll (R -O)2C, R C 00H or R JJHaI Example No. R R R R R X Y R CH3 H H H H H As per 001. 1 02H; H H C2115 Q-Bl' H D 0 CH CH CH CH H 7-CH O Do. a 1 CHa CaH1 CH 9-CuH H Do. H H 04H H H 7-CHa)2N Do H H H H H 8-OCH: Do C2115 CH3 CgH5 CH3 H 7-B! D0 H H CH3 H H S-F CH; OH; H H Q-OOH; H Do.

H H H H 9-F H D0 EXAMPLES 61 TO 70 Followin the rocedure of Example 7, substituting for the halogen deriv tive starting material of Example 7, the 45 amples 4l to 50 and the amlne heterocychc reactant halogen derivatives prepared in Examples 41 to 50 and shown in Column 1 of Table VI below, the product shown employing the alkanols set out in Column 1 of Table V Column 2 1S Obtalnfidbelow, the product shown in Column 2 of Table V is obtained.

TABLE V Column 1 Column 2 R R B NTO H Alkanol ROH R R R X Y H H H H H H H C2115 9-131 CH: CH3 CH3 H 7-CHsO CH3 CaH1 CH Q-CoH H C4110 H H 7-(CH3)2N H H H H 8-OCH CH; C H OH; H 7-Br CH H H 8-F H CH H H 9-0 CH:

EXAMPLES 81 TO 90 Following the procedure of Example 14, but substituting the 2,3-dihydro-1-hydroxyisoindolo[7,1,2-hij]quinolin- 5(lg)-one compounds of Examples 31 to 40 and the nitrile shown in column 1 of Table VII, the product shown Following the procedure of Example 18, but substituting as starting materials the halogennaphthostyril derivatives shown in column 1 of Table VIII below (prepared by reacting any of the compounds of Examples 3, 4 and 31-40 with a nitrile of the structure EXAMPLES 91 TO 100 in column 2 is obtained. 45 Hal(CH -CN TABLE VII R N O l Rfi-JI-NH R oN Example No. R R R R R R X Y 81 C3111 C 117 OH: H H H H H 82 CgH H H CzHl 9-31 H P-OCHa-CaHr- CHI CH CH3 CH1 H 7-CHgO p-ClCoH4- CaHz CH; C H1 CH1 9-C H H P-OH-CoHtp-OH-Cdh- H H 04H H H 7-(CH8)2N (CgH5)gNCaH4- p-(CzHshN-CuHt- H H H H H 8-OOH 87 \N m 0 H; CH C1111 CHI H 7-H! 88..-:.:-'..:. ClCHgCHr- ClCHgCHg- H H CH1 H H 8-]? 89....'.'..'.-.. CI\1: CH; CH: CH: H H Q-OCHr H NCHQCH, N CHgCH; c c

90-..'.-.:.. H H H H 9-1 H N-CHaCN N-CHaCN 17 where n is 1 to 4 as per the procedure of Examples 14 and 81 to 90) and the amine shown in column 2, the product shown in column 3 is obtained.

18 wherein X is NR O, S or CH r is 1, 2 or 3, R and R are each hydrogen, lower alkyl, hydroxy-lower alkyl, lower alkanoyloxy-lower alkyl, hydroxy-lower alkoxy- TABLE VIII Column 1 Column 2 Column 3 R4 R R R N O N 0 l 8 I n R 3)n fiNH Hl(CH) C NH R N (CH g Ex. N0. Hal 'n R R R R X Y HNPJR R R N 'n R R R R X Y 91 Cl 1 OH; H H H H H HN(CaH5)CH3 As per Col.2 As per Column 1.

92..." Br 2 0 11 H H can, 9-Br H .....do Do.

93 Br 3 CH CH CH CH5 H 7-CH O HN/ \S do D0.

94. C1 4 Ca 1 C8H7 3 u u H ...de Do.

95 I 2 H H OH H H 7- CH )zN do D0 4 9 a NH onmou 96 Br 3 H H H H H B-OCHa HNHClHo do Do.

97"... Br 2 CzHs CH C 13 OH; H 7-Br do D HN N-CIIg 98..-" Cl 2 H H CH H H 8-F HN(CH )C2H do D B 2 CH OH H H 9-OCH H o D 99 r a a 3 EN N-omomoi 100 C1 1 H H H H 9-F H HN/ .do Do.

What is claimed is: 1. A compound having the structure wherein X and Y are selected from the group consisting of hydrogen, halogen, nitro, lower alkyl, lower alkoxy, aryl and dimethylamino, and at least one of X and Y is hydrogen; R R R and R are the same or different and are selected from the group consisting of hydrogen and lower alkyl; R and R are the same or different and are selected from the group consisting of hydrogen, lower alkyl, aryl, and alkenyl of less than 8 carbon atoms, or R and R can be taken together with the nitrogen atom to which they are attached to form a heterocyclic ring having the formula:

References Cited UNITED STATES PATENTS 3,351,600 11/1967 Brack et al 260-288 FOREIGN PATENTS 662,237 8/ 1965 Belgium.

G. THOMAS TODD, Primary Examiner US. Cl. X.R.

260-243 B, 268 PC, 287 R, 288 R, 289 R, 326.27; 424- 246, 248, 262

I I UNITED STATES PATENT OF CERTIFICATE CORRECTION Patent No. 3,819,624 Dated June 25, 1974 InventoflS) Seymour D. Levine It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 6, lines 37 to 45, the structure should be labeled:

-- XVI Column 9, line 26, that portion reading: "N, 9,49" should be:

Column 13, Example 59, Column R the structure should read:

Column 14, Example 55, Column Y, insert a left parenthesis after "7-" but before CH N. Column 15, Example 73, Column HNR R after the right parenthesis delete the following: CH and insert in its place: CH A 1 Column 18, Example 9 5, Column HNR R the structure should read:

HMO- (CH2) 20H Signed and sealed this 1st day of October 1974.

(SEAL) attest:

MCCOY M. GIBSON JR. 0. MARSHALL DANN I Attesting Officer Commissioner of Patents FORM 1 0-1050 (10-69) USCOMM-DC GO376-P69 U,5: GOVERNMENT PRINTING OFFICE: I569 O-366-384. 

